Enamine

Formation

:[[File:Enamine.png|thumb|center|320px|Condensation to give an enamine.]] Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by condensation of secondary amines with ketones and aldehydes.. The condensing ketone and aldehyde must contain an α-hydrogen. The associated equations for enamine formation follow: : (carbonolamine formation) : (enamine formation)

In some cases, acid-catalysts are employed. Acid catalysis is not always required, if the pKaH of the reacting amine is sufficiently high (for example, pyrrolidine, which has a pKaH of 11.26). If the pKaH of the reacting amine is low, however, then acid catalysis is required through both the addition and the dehydration steps. Common dehydrating agents include MgSO4 and Na2SO4.

Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of TiCl4 into the reaction mixture (to act as a water scavenger).

Primary amines are usually not used for enamine synthesis. Instead, such reactions give imines: : (carbonolamine formation) : (imine formation) Imines are tautomers of enamines. The enamine-imine tautomerism is analogous to the keto-enol tautomerism.

Structure

As shown by X-ray crystallography, the portion of enamines is close to planar. This arrangement reflects the sp2 hybridization of the core.

E vs Z geometry affects the reactivity of enamines.

Reactions

Enamines are nucleophiles. Ketone enamines are more nucleophilic than their aldehyde counterparts.

Compared to their enolate counterparts, their alkylations often proceed with fewer side reactions. Cyclic ketone enamines follow a reactivity trend where the five membered ring is the most reactive due to its maximally planar conformation at the nitrogen, following the trend 5867 (the seven membered ring being the least reactive). This trend has been attributed to the amount of p-character on the nitrogen lone pair orbital - the higher p character corresponding to a greater nucleophilicity because the p-orbital would allow for donation into the alkene π- orbital. Analogously, if the N lone pair participates in stereoelectronic interactions on the amine moiety, the lone pair will pop out of the plane (will pyramidalize) and compromise donation into the adjacent π C-C bond.

Alkylation and acylation

Alkylation is the predominant reaction sought with enamines. When treated with alkyl halides enamines give the alkylated iminium salts, which then can be hydrolyzes to regenerate a ketone (a starting material in enamine synthesis): : (alkylation of enamine) : (hydrolysis of the resulting iminium salt, giving a 2-alkylated aldehyde) Owing to the pioneering work by Gilbert Stork, this reaction is sometimes referred to as the Stork enamine alkylation. Analogously, this reaction can be used as an effective means of acylation. A variety of alkylating and acylating agents including benzylic, allylic halides can be used in this reaction.

Similar to their alkylation, enamines can be acylated. Hydrolysis of this acylated imine forms a 1,3-dicarbonyl.{{cite journal |doi=10.15227/orgsyn.043.0034 |title=Docosanedioic Acid |journal=Organic Syntheses |date=1963 |volume=43 |page=34|author=S. Hunig, E. Lucke, W. Brenninger : (acylation of enamine) : (hydrolysis of the resulting acyl iminium salt, giving a C-acylated aldehyde)

Halogenation

Chlorination of enamines followed by hydrolysis gives α-halo ketones and aldehydes: : (chlorination of enamine) : (hydrolysis of chloroiminium, giving a chloroaldehyde) In addition to chlorination, bromination and even iodination have been demonstrated.

Oxidative coupling

Enamines can be efficiently cross-coupled with enol silanes through treatment with ceric ammonium nitrate. Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final pyrrole formation. This method for symmetric pyrrole synthesis was developed in 2010 by the Jia group, as a valuable new pathway for the synthesis of pyrrole-containing natural products.

Annulation

Enamines chemistry has been implemented for the purposes of producing a one-pot enantioselective version of the Robinson annulation. The Robinson annulation, published by Robert Robinson in 1935, is a base-catalyzed reaction that combines a ketone and a methyl vinyl ketone (commonly abbreviated to MVK) to form a cyclohexenone fused ring system. This reaction may be catalyzed by proline to proceed through chiral enamine intermediates which allow for good stereoselectivity. This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the Wieland-Miescher ketone – a vital building block for more complex biologically active molecules.

Metalloenamines

Lithiated enamines (also known as aza enolates, imine anions, enamides, or metallated Schiff bases) are nitrogen analogues to enolates, formed when imines get treated with strong bases such as LiNR2:

They can also be formed with Grignard reagents and react with other soft electrophiles, including Michael receptors.

Aza enolates are highly nucleophilic at the β carbon, but scarcely electrophilic. They do not undergo self-condensation in a basic or neutral solution (where aldehydes would undergo the aldol reaction). Thus, aza enolates are convenient to alkylate the β carbon with epoxides and alkyl halides:

That reaction is one of the key steps in the synthesis of the Oulema melanopus' male aggression pheromone:

Most prominently, these reactions have allowed for asymmetric alkylations of ketones through transformation to chiral intermediate metalloenamines.

Biochemistry

Nature processes (makes and degrades) sugars using enzymes called aldolases. These enzymes act by reversible formation of enamines.

References

References

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